Mechanistic insights into metal ions transit through threefold ferritin channel

Background: The mechanism of how the hydrophilic threefold channel (C3) of ferritin nanocages facilitates diffusion of diverse metal ions into the internal cavity remains poorly explored. Methods: Computational modeling and free energy estimations were carried out on R. catesbeiana H´ ferritin. Transit features and associated energetics for Fe2+, Mg2+, Zn2+ ions through the C3 channel have been examined. Results: We highlight that iron conduction requires the involvement of two Fe2+ ions in the channel. In such doubly occupied configuration, as observed in X-ray structures, Fe2+ is displaced from the internal site (stabilized by D127) at lower energetic cost. Moreover, comparison of Fe2+, Mg2+ and Zn2+ transit features shows that E130 geometric constriction provides not only an electrostatic anchor to the incoming ions but also differentially influence their diffusion kinetics. Conclusions: Overall, the study provides insights into Fe2+ entry mechanism and characteristic features of metal-protein interactions that influence the metal ions passage. The dynamics data suggest that E130 may act as a metal selectivity gate. This implicates an ion-specific entry mechanism through the channel with the distinct diffusion kinetics being the discriminating factor.